New molecular mechanism underlying myc-mediated cytochrome P450 2E1 upregulation in apoptosis and energy metabolism in the myocardium

Abstract

Background-—Canonical studies indicate that cytochrome P450 2E1 (CYP2E1) plays a critical role in the metabolism of xenobiotics and ultimately participates in tissue damage. CYP2E1 upregulates in the pathophysiological development of multiple diseases; however, the mechanism of CYP2E1 upregulation, particularly in heart disease, remains elusive. Methods and Results-—We found that the level of CYP2E1 increased in heart tissues from patients with hypertrophic cardiomyopathy; multiple mouse models of heart diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and myocardial ischemia; and HL-1 myocytes under stress. We determined that Myc bound to the CYP2E1 promoter and activated its transcription by bioinformatics analysis, luciferase activity, and chromatin immunoprecipitation, and Myc expression was modulated by extracellular signal–regulated kinases 1/2 and phosphatidylinositol 3 kinase/protein kinase B pathways under stress or injury in myocardium by signal transduction analysis. In addition, the level of oxidative stress and apoptosis gradually worsened with age in transgenic mice overexpressing CYP2E1, which was significantly inhibited with CYP2E1 knockdown. Conclusions-—Our results demonstrated that CYP2E1 is likely a sensor of diverse pathophysiological factors and states in the myocardium. Upregulated CYP2E1 has multiple pathophysiological roles in the heart, including increased oxidative stress and apoptosis as well as energy supply to meet the energy demand of the heart in certain disease states. Our discovery thus provides a basis for a therapeutic strategy for heart diseases targeting Myc and CYP2E1.